Activation of P53 by Nutlin Leads to Rapid Differentiation of Human Embryonic Stem Cells
Oncogene (2008) 27, 5277–5287 & 2008 Macmillan Publishers Limited All rights reserved 0950-9232/08 $32.00 www.nature.com/onc ORIGINAL ARTICLE Activation of p53 by nutlin leads to rapid differentiation of human embryonic stem cells T Maimets1,2, I Neganova2,3, L Armstrong2,3 and M Lako2,3 1Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia; 2Institute of Human Genetics, University of Newcastle, Newcastle upon Tyne, UK and 3North East Stem Cell Institute, University of Newcastle, Newcastle upon Tyne, UK p53 is an important regulator of normal cell response to transition mechanisms remain largely obscure. One stress and frequently mutated in human tumours. Here, we possibility to clarify these relationships is to study the studied the effects of activation of p53 and its target activity of important components of signal-transduction gene p21 in human embryonic stem cells. We show that pathways—oncogenes and tumour suppressor genes—in activation of p53 with small-molecule activator nutlin each of these cell types. Several oncogenes and tumour leads to rapid differentiation of stem cells evidenced by suppressors, such as Bmi1 (Molofsky et al., 2003), Gfi1 changes in cell morphology and adhesion, expression of (Hock et al., 2004), Pten (Groszer et al., 2001), Wnt/ cell-specific markers for primitive endoderm and trophec- beta-catenin (Dravid et al., 2005) and Notch (Dontu toderm lineages and loss of pluripotency markers. p21 is et al., 2004), have been shown to control the self-renewal quickly and dose-dependently activated by nutlin. It can of normal untransformed tissue stem cells. also be activated independently from p53 by sodium p53 gene is mutated in more than half of human butyrate, which leads to the differentiation events very tumours (Hainaut and Hollstein, 2000), which indicates similar to the ones induced by p53.
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